Versatile Picklocks To Access All Opioid Receptors: Tuning the Selectivity and Functional Profile of the Cyclotetrapeptide c[Phe-D-Pro-Phe-Trp] (CJ-15,208)

Recently, the tryptophan-containing,noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed x/mu-ligand c[Phe-b-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and. agonism/ antagonism varied upon enlarging macrocycle size, giving the mu-agonist 9 or the delta-antagonist 10 characterized by low nanomolar affinity. In particular, the mu-agonist c[beta-Ala-D-Pro- Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration.